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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1114-1120.
Prepublished online as a Blood First Edition Paper on October 14, 2004; DOI 10.1182/blood-2004-07-2561.
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Submitted July 9, 2004
Accepted August 30, 2004
Anti-human CTLA-4 monoclonal antibody promotes T cell expansion and immunity in a hu-PBL-SCID model: a new method for preclinical screening of costimulatory monoclonal antibodies
Kenneth F May, Sameek Roychowdhury, Darshna Bhatt, Ergun Kocak, Xue-Feng Bai, Jin-Qing Liu, Amy K Ferketich, Edward W Martin, Michael A Caligiuri, Pan Zheng, and Yang Liu*
Division of Cancer Immunology, Department of Pathology, The Ohio State University Medical Center and Comprehensive Cancer Center, Columbus, OH, USA
Division of Hematology/Oncology, Department of Internal Medicine, The Ohio State University Medical Center and Comprehensive Cancer Center, Columbus, OH, USA
Division of Epidemiology and Biometrics, The Ohio State University Medical Center and Comprehensive Cancer Center, Columbus, OH, USA
Division of Surgical Oncology, Department of Surgery, The Ohio State University Medical Center and Comprehensive Cancer Center, Columbus, OH, USA
* Corresponding author; email: liu-3{at}medctr.osu.edu.
When adopting basic principles learned in mice to clinical application in humans, it is often difficult to distinguish whether a failed "translation" is due to an invalid target in the human disease or because the therapeutic agents are not optimal for the human target. It is therefore desirable to develop preclinical models to optimize therapies for human targets using in vivo settings. Although anti-mouse CTLA-4 antibodies are known to enhance immune responses in vivo, their effect on T cell activation in vitro ranges from enhancement to inhibition. Here we use the hu-PBL-SCID mouse model of EBV-associated lymphoma development to screen a panel of anti-human CTLA-4 mAbs for their effect on human lymphocytes in an in vivo "humanized" environment. We report significant heterogeneity of anti-human CTLA-4 mAb in enhancing expansion of human T cells in mice, and this heterogeneity cannot be attributed to Ig isotypes or affinity for CTLA-4. These data validate the development of additional screening tools such as the one described, to further characterize functional activity of anti-human antibodies before proceeding with clinical translation to human studies.
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